Barriers and facilitators to anti-retroviral therapy adherence among adolescents aged 10 to 19 years living with HIV in sub-Saharan Africa: A mixed-methods systematic review and meta-analysis

Background Human Immunodeficiency Virus (HIV) significantly affects adolescents globally, with the sub-Saharan Africa (SSA) reporting a high burden of the disease. HIV testing, treatment, and retention to care are low among adolescents. We conducted a mixed-method systematic review to assess anti-retroviral therapy (ART) adherence; barriers and facilitators to ART adherence and ART outcomes among adolescents living with HIV and on ART in sub-Saharan Africa. Methods We conducted searches in four scientific databases for studies conducted between 2010 and March 2022 to identify relevant primary studies. Studies were screened against inclusion criteria and assessed for quality, and data was extracted. Meta-analysis of rates and odd ratios was used to plot the quantitative studies and meta-synthesis summarized the evidence from qualitative studies. Results A total of 10 431 studies were identified and screened against the inclusion/ exclusion criteria. Sixty-six studies met the inclusion criteria (41 quantitative, 16 qualitative, and 9 mixed-methods study designs). Fifty-three thousand two hundred and seventeen (53 217) adolescents (52 319 in quantitative studies and 899 in qualitative studies) were included in the review. Thirteen support focused interventions for improved ART adherence were identified from quantitative studies. The plotted results from the meta-analysis found an ART adherence rate of 65% (95%CI 56–74), viral load suppression was 55% (95%CI 46–64), un-suppressed viral load rate of 41% (95%CI 32–50), and loss to follow up of 17% (95%CI 10–24) among adolescents. Meta-synthesis found six themes of barriers to ART (social, patient-based, economic, health system-based, therapy-based, and cultural barriers) in both the qualitative and quantitative studies, and three themes of facilitators to ART were also identified (social support, counselling, and ART education and secrecy or confidentiality) from qualitative studies. Conclusion ART adherence remains low among adolescents in SSA despite multiple interventions implemented to improve ART adherence. The low adherence rate may hinder the attainment of the UNAIDS 2030 targets. Additionally, various barriers to ART adherence due to lack of support have been reported among this age group. However, interventions aimed at improving social support, educating, and counselling adolescents may improve and sustain ART adherence. Trial registration Systematic review registration: PROSPERO CRD42021284891.

adherence rate of 65% (95%CI 56-74), viral load suppression was 55% (95%CI 46-64), unsuppressed viral load rate of 41% (95%CI 32- 50), and loss to follow up of 17% (95%CI 10-24) among adolescents. Meta-synthesis found six themes of barriers to ART (social, patient-based, economic, health system-based, therapy-based, and cultural barriers) in both the qualitative and quantitative studies, and three themes of facilitators to ART were also identified (social support, counselling, and ART education and secrecy or confidentiality) from qualitative studies.

Conclusion
ART adherence remains low among adolescents in SSA despite multiple interventions implemented to improve ART adherence. The low adherence rate may hinder the attainment of the UNAIDS 2030 targets. Additionally, various barriers to ART adherence due to lack of support have been reported among this age group. However, interventions aimed at improving social support, educating, and counselling adolescents may improve and sustain ART adherence.

Trial registration
Systematic review registration: PROSPERO CRD42021284891.

Background
Adolescents are the most affected age group globally, with 1.75 million (1.16-2.3 million) of adolescents living with HIV (ALHIV) and 90% of these adolescents are found in the sub-Saharan Africa (SSA) region by July 2021 [1]. In 2020, adolescents accounted for 11% of new infections and 5% of AIDS-related deaths globally [2]. HIV testing is low among adolescents, especially in SSA countries. In a study conducted by Asaolu et al.,26.5% of adolescents aged 15 to 19-years had ever tested for HIV in sub-Saharan Africa, thus the proportion of those living with HIV and on treatment is low [3]. HIV treatment outcomes such as viral load suppression and AIDS-related death rate are also poor among adolescents due to low retention to care and poor treatment adherence rate [4,5]. Accordingly, viral load suppression is low among adolescents when compared to adult population [6].
Viral load suppression (VLS) defined as viral load <50 RNA copies per ml of blood is associated with optimum ART adherence [7]. Optimum ART adherence is defined as correctly taking of medication doses above 95% [8]. Among adolescents, ART adherence is reported to be low and even lower in the SSA region. The sub-optimum adherence (less than 95% of correctly taking medication) is as a result of a number of factors namely; social, economic, therapyrelated and health system-related and patient-related barriers [9].
Several interventions have been implemented to counteract these barriers and thus facilitate ART adherence among people living with HIV. These interventions are mainly focused in improving social support through the use of reminders and peers [10,11]. Additionally, interventions aimed at improving facility-based barriers such as ART clinics and combination therapy have been implemented yielding positive ART treatment outcomes [12,13]. World Health Organization guidelines have enabled the improved diagnosis and treatment initiation of people living with HIV. These include the 2010 guidelines which broadened the eligibility to ART to CD4 count of �350 cells/mm 3 for all regardless of the clinical stage [14].
Targets aimed at collective effort to improve clinical outcomes have also been set such as the fast-track commitments by UNAIDS. These are the 90% reduction of new HIV cases by the year 2030 and the 61% reduction in HIV prevalence between 2010 and 2050 [15,16]. Additionally, the fast-track 2030 targets aiming at 95% of those living with HIV knowing their HIV status, 95% of them on ART and 95% of those on ART with suppressed viral load. However, adolescents in the SSA region present poor outcomes as 43% are initiated on ART treatment with only 31% of those initiated on ART continue to access ART. Among those continually accessing ART, 30% are viral load suppressed [17,18].
The COVID-19 pandemic has further negatively influenced HIV outcomes globally [19,20]. For instance, in 2018, viral load suppression among those on ART was 58% increasing to 72% in 2020 [21,22]. In 2021, globally, there was a reduction in viral load suppression rate among those on ART globally as it was 66% from 72% in 2020 [23]. Even though adolescent data is scanty, studies comparing viral load suppression rate pre-COVID-19 and during the pandemic have generally indicated a decrease in VLS. For instance, a study conducted in Durban, South Africa in 2020 among ALHIV, VLS was 98.5% pre-COVID-19 and dropped to 83.6% during the COVID-19 period [24]. The reduction in VLS was also seen in a study conducted in Atlanta [25]. However, a study conducted in the Democratic Republic of Congo a study reported an increase in VLS during COVID-19 pandemic especially in rural [26]. The increase was a result of closeness to health facilities, the differentiated care model change from monthly refill to multi-months refill cutting transport costs and clinical factors [26]. Nevertheless, the general drop in VLS among ALHIV is an indication of poor ART adherence during the COVID-19 pandemic due to lockdowns [27][28][29][30][31].
As a result of the lockdowns, there were disruptions in access to HIV prevention and control services resulting in new infections and severe HIV treatment outcomes, especially among adolescents from SSA [24,26,[32][33][34]. Within SSA, COVID-19 prevention and treatment options were limited with low vaccination coverage of 3% yet COVID-19 infection has been associated with severe outcomes among people living with HIV [1,[19][20][21]. Studies on impact of COVID-19 among adolescents by members of the Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA) program revealed that the COVID-19 pandemic threatened the accessibility and availability of ART for adolescents [31,35]. The lockdowns restricted access to health care facilities for refills, clinical support such as counselling session and other social support programs [27,28,35]. Secondly, healthcare workers were re-deployed in COVID-19 program thus reducing the number of staff members resulting to under-staffing [27,29]. Thirdly, funding was re-directed to COVID-19 programs while HIV programs were affected resulting to adolescents' programs stalled [27,29]. Furthermore, loss of income and restriction on travel due to COVID-19 lockdowns impacted on ART access and adherence as there were no transport and funds for transport costs to health facilities [27][28][29]35]. In a study conducted in 2022 among ALHIV and on ART in South Africa revealed that COVID-19 lockdown restrictions have been associated with mental health problems among adolescents living with HIV as a result of the isolation, quarantine, closing of schools which reduced the support systems for adolescents especially from schools and peers [30,33,36,37]. Lastly, COVID-19 prevention and control strategies have been associated with social isolation, loss to follow up and poor ART adherence due to food insecurity and poverty as a result of the COVID-19 pandemic [27,32,35].
Nevertheless, advances had been made pre-COVID-19 pandemic in the control and prevention of HIV yet adolescents still presented poor HIV treatment outcomes [18]. There is scanty comprehensive adolescent-focused data on the barriers, facilitators of ART adherence, and HIV treatment outcomes in SSA even pre-COVID-19 pandemic. Therefore, our review aimed at systematically and critically reviewing literature on ART adherence among adolescents living with HIV (ALHIV) in SSA by exploring evidence on: (a) the barriers and facilitators of ART adherence; (b) ART outcomes (ART adherence rate, loss to follow up, viral load suppression and non-suppression rates); (c) Types of interventions aimed at improved ART adherence among ALHIV from SSA.

Methods
The systematic review is registered with PROSPERO (Registration: CRD42021284891) [38]. The results are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement) [39], and the Enhancing Transparency in Reporting the synthesis of Qualitative research (ENTREQ) recommendations [40].

Search strategies
A literature search including only studies conducted from 2010 to March 2022 was conducted. The following databases were used for this literature search; PubMed, Cochrane Review, Scopus on Excerpta Medica Database (Embase) and CINAHL.
To identify studies, the following search terms were used: (Antiretroviral OR ART) AND (adherence Or Compliance) AND (Adolescents) AND (sub-Saharan Africa* OR sub-Saharan Africa region). Full search terms are found in S1 Table. The inclusion criteria were research studies (qualitative, quantitative, and mixed method research studies) reporting on ART adherence outcomes among adolescents aged 10 to 19-years in sub-Saharan Africa. We only included English published articles. The following outcomes were included: • ART adherence rate: proportion of adolescents with optimum ART adherence among total adolescent in the study • ART adherence barriers: list and proportion of adolescents reporting either patient or individual, economic, social, health system-related, therapy-related and cultural barriers faced by participants in attaining optimum ART adherence [9,41,42].
• Lost to follow up (LTFU): proportion adolescents lost to follow up.

Study selection
Two investigators (LDH and JLT) independently assessed studies citations against the inclusion criteria. For citations where there was eligibility disagreement, PSN further independently resolved the disagreements. LDH and JLT further independently assessed included studies for eligibility through reading through the full text and disagreements were resolved through consensus between the two investigators. The review process is attached as Fig 1.

Data extraction
We imported search outputs into Covidence library and removed duplicate references. Two data extraction forms were designed for quantitative and qualitative study designs. Mixed methods data extraction was conducted as separated in quantitative and qualitative designs. LDH and JLT independently extracted descriptive and analytical data from included studies (Tables 1 and 2). Extracted data included the following: Author (s), title, year of publication, country, study design, study characteristics, participants demographic data, type of intervention, themes or outcomes, and final findings. Secondly, barriers to ART adherence were grouped into patient-related, therapy-related, health system-related, social, economic, and cultural factors (9) (Tables 3 and 4). Lastly, facilitators to ART adherence were extracted from each included qualitative study ( Table 5). Consensus of data extraction was obtained through discussions between JLT and LDH and JLT finally went through all citations and data extracted to ensure accuracy. In case of any discrepancy, PSN was consulted. Upon consensus on qualified studies, LDH and JLT entered relevant data for the excel data extraction forms from potentially eligible studies. Strengthening the reporting of epidemiological studies (STROBE) and the Consolidated Qualitative Study (COREQ) Reporting Standards for both quantitative and qualitative studies have guided the design of these types of forms [43].

Critical appraisal
Study quality was independently assessed by LDH and JLT through using methodological quality criteria outlined for qualitative, quantitative and mixed method studies in the Mixed Method Appraisal Tool (MMAT) [44]. Qualitative studies were assessed using the following five domains: a) appropriateness of the approach in answering research question b) adequacy of data collection methods to answer research question c) if findings were derived from data presented d) interpretation of results sufficiently validated by data and e) coherence between data sources, collection, analysis, and interpretation. Quantitative studies were assessed based on either as randomized control trials, non-randomized or descriptive studies. For randomized control trials the following domains were used; a) randomization, b) comparability of the groups, c) completeness of outcome data, d) blinding of assessors and e) adherence to intervention by participants. Non-randomized trials were assessed against a) appropriateness of the measurements, b) representativeness of target population, c) completeness of outcome data, d) controlling for confounder at design, analysis, and e) if intervention was administered as intended. On the other hand, descriptive quantitative studies were assessed for: a) relevancy of sampling strategy, b) representativeness of target population, c) appropriateness of measurements, d) level of risk of bias and e) appropriateness of statistical analysis. Lastly, mixed method studies were assessed for: a) rationale for used the design, b) integration of the two different components, c) interpretation of the outputs of the integrated components, d) if discrepancy and inconsistences between the two components were addressed and e) if the two components adhered to quality criteria of each component. The final scores for the assessment were agreed through discussions between LDH and JLT. PSN subsequently resolved conflicts via discussion with the dual screeners.      Cross-sectional None Older ALWHIV with high ART adherence self-efficacy were eight times more likely to report high adherence and those on a twice a day ART regimen were almost four times more likely to report adherence. Self-esteem, age, sex, schooling, perceived social support and experienced stigma were not found to be associated with adherence among these older adolescents.

Statistical analysis
Data analysis was done through parallel results convergent design where qualitative and quantitative findings were analyzed separately and integrated in the overall results. For quantitative analysis, a meta-analysis was conducted using Stata software version 16 and Open Meta analyst. Meta-analysis was performed to calculate the pooled estimates of the following outcomes: ART adherence, viral load suppression, unsuppressed viral load, and loss to follow up. The pooled effect size was calculated as rates and the odds ratios and their 95%CIs. As we expected high heterogeneity between studies, subgroup analysis was undertaken based on different ART barriers reported in the studies. In addition, we also performed meta-regression based on the adolescents' age groups. A random effect meta-analysis was used to pool the estimates because of the variability of study designs and interventions. Heterogeneity was quantified using the I 2 to identify study variation. Furthermore, publication bias was used to assess to the funnel plot symmetry and the Egger rank and Begg correlation tests were used to assess the quantitative publication bias. For statistical analysis, P-values of 0.05 were considered statistically significant. As Stata software version 16 reported the Log OR, we converted this to the OR. Qualitative analysis was conducted through grouping key finding into the main themes according to both the barriers and facilitators to ART adherence as relevant to the study (Tables 4 and 5). Similarly, barriers to ART adherence were analyzed for quantitative design studies narratively through grouping findings into main barriers to ART themes ( Table 3). The themes used in this study were patient-related, social, therapy-related, health systemrelated, economic, and cultural barriers [9]. These themes were then subjected to a meta-synthesis to produce a single comprehensive set of synthesized findings.

Results
A total of 10 431 studies were found after running the search strategy in the different databases and 4744 duplicates were removed. The process followed the PRISMA guidelines as reported in Fig 1. Only 206 full-text studies met screening criteria and 66 studies retained and were included in the analysis: quantitative studies (n = 41), qualitative studies (n = 16), and mixed study (n = 9). Other studies were excluded because of wrong data collection period, wrong population group, non-disintegrated by age and one study was excluded because of its small sample size.

Characteristic of included studies
Out of the 66 studies included, 24 studies were included for the qualitative analysis of which 8 (out of the 9 mixed methods studies, 8 were included in the qualitative analysis as one study did not report on the outcome of interest in the qualitative component but only the quantitative component) of these were the qualitative component of mixed-method studies as reported in Table 1. Most studies (7/24) included adolescents aged 10 to 19 years followed by 13 to 19-year-old (4/24) and 12 to 19-year-old (3/24). Majority (5/24) of the studies were conducted in South Africa followed by Kenya (4/24). The other studies originated from the following   (Table 2), 48 studies were included in the meta-analysis of which 7 were the quantitative component of the mixed method studies (two mixed method studies were not included in the quantitative analysis since in their quantitative component, study population was not disaggregated by age but were only disaggregated in the qualitative component was included in this study). Majority of the studies (29) studies included adolescents aged 10 to 19 followed by 4 studies with adolescents aged 15 to 19 years. Twenty-one studies were cross-sectional in design while 19 were cohort studies. Nine studies were conducted in South Africa and another 9 in Zimbabwe followed by 7 studies conducted in Uganda. The other studies were conducted in the following countries: Kenya (5); Zambia (3);

Quality assessment
The results of the quality assessment are shown in the S2 Table. For each domain, the score was "yes or no," and a percentage of the "yeses" was used as the final score for each study. Among the qualitative studies, only one study scored less than 50% [45], two scored 60% [44,45] and the remaining thirteen were scored 80 and above [41, 46-

Barriers to ART adherence.
Six categories of barriers to ART were reported in included studies. These were social, economic, health systems-related, therapy-related, patient-related and cultural barriers as adopted from previous studies [9]. Table 3 shows the barriers presented in the included studies.
Additionally, seven studies reported on interventions reporting ART adherence barriers and VLS [64, 73,76,77,81,93,108]. VLS was not statistical associated with the barriers to ART (OR 1.25 (95% CI 1-1.55 p = 0.05: I 2 61.1%)). However, in a study conducted in Zimbabwe, health systems and therapy-related barriers were associated with over two-fold increase in viral load suppression (OR 2.  [81] were not associated with VLS (Fig 6).

Meta regression
A meta-regression analysis was performed to examine the ART the relationship between ART adherence and age group. ART adherence statistically reduced in the age group of 10 to 16 and 10 to 18 with P = 0.002 and 0.005, respectively. In contrast, a borderline decreased of adherence was observed in the age group of 10-19 years, P = 0.056 (Table 6).

Publication bias
The visual inspection of the funnel plots including ART adherence, viral load suppression and unsuppressed viral load rates were asymmetric (Figs 10-12). However, the Egger's tests for small study effects and Begg's test for ART adherence, viral load suppression and unsuppressed viral load rates were not statistically significant with the p-values of 0.2737; 0.3938, and 0.6147, respectively. Based on the above, publication bias may be considered less likely. 3.7. Meta-synthesis 3.7.1. Barriers of ART adherence. Social barriers: Stigma and discrimination and lack of social support were the mostly identified social barriers to ART adherence among adolescents. Stigma and discrimination emanated from family members including parents and care-givers, community, friends, partners and school mates resulting to mental health effects such as depression and being suicidal [42, 45-47, 49, 50, 56, 57, 59, 100, 102, 103, 108, 109, 113]. While lack of support from caregivers and school mechanism resulted in adolescents being resentful and thus influenced their ART adherence patterns and resulting to hopelessness and suicidal thoughts too [49,109,113]. Lack of social support was evident among adolescents with a nonparent caregiver [42,46,49,54,55,58,106]. Within the school mechanism, studies reported the clash in medicine taking time, classes, exams or tests period, living environment for those in boarding schools, busy schedule and the appointment time at the health facilities as barriers to ART adherence [45, 49-52, 55, 56, 58, 59, 103, 104, 110].
Economic barriers: Poverty was reported to influence the ART adherence pattern among ALHIV. Poverty as explained in terms of lack of transport money to honor clinic schedules and lack of water and food to facilitate the correct uptake of medication resulted to adolescents missing clinic appointments and stopping medication [42,51,55,58,59,104,105].
Heath system-related barriers: Clinic or health facility factors were identified by adolescents as a barrier to ART adherence as a result of the location and distance to heath facility, waiting time at the facility, overcrowding, stock out, clinic protocols such as color coding, attitude of healthcare workers, and rigid scheduling of appointments [40,47,49,50,52,56,104,110]. These factors influenced the ART adherence patterns of the adolescents as they were not supportive to the needs of ALHIV resulting in loss to follow up and defaulting of medication [47,110].
Therapy-related barriers: Regime, dosage frequency and side effects of medication were reported as the main barriers of ART adherence related to the treatment resulting to adolescents stopping medication [42,46,47,[50][51][52]57]. Additionally, adolescents complained about the packaging of the pills as it was easy to identify what it is due to the labelling and also the bottles were large and made lots of noise risking unintended disclosure of their status and treatment [54,57].
Patient-related barriers: The attitude of adolescents, adolescents' responsibility for treatment, and the ART knowledge were also a barrier to ART adherence as adolescents felt that being on ART posed restrictions on their life and caused them to miss opportunities their peers had [49,54,102]. Additionally, forgetfulness, tiredness, being busy, fatigue, being away from home were reported to also hinders adolescents' ART adherence [42,46,50,52,56,58,59,102,104,106]. Adolescents stated that they also want to feel like others and just take pill holidays so they feel normal [106]. Lastly, adolescents described how not knowing what the medication, misconceptions and myths about ART made them less interested in adhering to taking it [102,104]. Cultural barriers: Religion and culture had a strong influence on ART adherence among adolescents as they stopped taking their medication because they were prayed for, and were told to believe they were healed or believed that traditional medicine will heal them [55, 104].

Facilitators of ART adherence.
Adolescents identified three themes to be important in promoting adherence to ART. These were support, secrecy or confidentiality and counselling or education. The facilitators are presented in Table 5. Social Support: Multiple studies reported that support system emanated from peers, family members, school, health facility, financial and personal or interpersonal support [46-48, 50, 51, 53, 57, 59, 104, 108, 109, 114],. These were fundamentals in mitigating stigma, discrimination and isolation and thereby foster networks and connectiveness of adolescents and their peers while creating a support structure to encourage adolescents to adhere to their medication especially when they are fatigued [42, 45, 47, 49, 51, 53, 54, 56-59, 100, 102, 104, 106, 109, 113]. Lastly, financial support was reported to be critical in ensuring adolescents had access to and could adhere to medication through provision of transport to the clinic and food supply [47,53,102,104].
Secrecy or confidentiality: Status disclosure and safe storage of medication were reported to positively influence ART adherence as they enabled adolescents to take charge of their lives through adhering to the treatment as they understand the benefits of the medication [45,50,52,54,100,110].  Counselling and ART education: This gives adolescents an understanding of their status and importance of adhering while allaying their anxiety and discarding myths and misconceptions [42,45,49,51, 100, 103, 106].

Overall results
An ART adherence rate of 65% (95% CI 56-74) was reported among adolescents in the SSA region. Viral load suppression rate was 55% (95% CI 46-64) while an unsuppressed viral load rate of 41% (95% CI 32-50) was reported with 17% (95% CI 10-24) loss to follow up rate. Six themes of barriers to ART adherence were identified among adolescents in SSA. These were social barriers, economic barriers, patient-related barriers, health systems-related and cultural barriers. Lastly, three main facilitating factors were identified being social support, secrecy or confidentiality and counselling, and ART education. The findings also revealed that the more barriers reported, the lower the adherence to ART among adolescents. According to the metaregression, ART adherence was lower in the age group of 10 to 18 years. Poor ART adherence was caused by a composite of social and patient-related barriers. Adolescents had lower viral load suppression and a high rate of un-suppression due to social, health system, and patientrelated barriers. Finally, health system and patient-related barriers reported a high rate of follow-up loss among adolescents. In comparison to the poor impact of interventions (SMS reminders, community adherence supporters, and teen clubs) on ART adherence, ART adherence facilitators have proven to be effective and acceptable among HIV-infected adolescents.

Discussion
The systematic review identified 66 studies which were included in the analysis which expanded on prior review on the same topic; ART adherence among adolescents [115][116][117]. The findings of our review showed that ART adherence was 65% (95% CI 56-74) and viral suppression was 55% (95% CI 46-64) which was in consistence with the 62% viral suppression used as a proxy measure for ART adherence among adolescent globally as reported in a systematic review including 53 countries [116]. There was a statistically positive association between ART adherence and adolescents age groups inclusive of the 10 to14 year age group. ART adherence was statistically poor among older adolescents which is comparable with studies reporting higher adherence among younger adolescents (10 to 14 years) compared to older adolescents (15 to 19 years). This could be explained by caregivers having higher levels of selfefficacy for medical care engagement and having good physician-caregiver relationships in early adolescence. In contrast, physical and social environments such as hostels for older adolescents' students, and stigma may play a substantial role in poor ART adherence in older adolescents. Furthermore, substance abuse may be a major factor in poor adherence in this age group. Studies have attributed the decrease in ART adherence among older adolescents to the diminishing support from care-givers during the transition from childhood to young adult and lack of second line ART especially in resource limited settings [42,[118][119][120]. However, the findings reported lower VLS rates compared to 2012 findings where VLS was at 84% in low-and middle-income countries yet was in consistent with findings of a systematic review reporting 59% in SSA [121]. Secondly, loss to follow up in our review was 17% (95% CI 10-24) which is lower to findings of a study conducted in 34 countries under the International epidemiology Database to Evaluate AIDS (IeDEA) where LTFU was reported to be 30% in 2018 [122]. Loss to follow up rate in this review indicate improvement when compared to studies conducted in 2007 in SSA where LTFU was 51% [123]. Additionally, our findings revealed that unsuppressed viral load is 41% in SSA countries which is higher than reported rates between 15.5% and 16.6 to 25.6% reported in Uganda and South Africa respectively [122,123].
This however can be explained by findings of a systematic review conducted by Munyayi et al whereby different adolescent's focused intervention to improve ART adherence among countries reported differing viral load outcomes [124]. Lastly, interventions for ART adherence in included studies were primarily support oriented similar to findings to studies conducted in middle-and low-income countries even though our study indicated an increase in the number of interventions compared to previous studies [4,13,115]. However, our findings show that interventions such as SMS reminders, community adherence supporters, and teen clubs did not improve ART adherence in adolescents. In contrast, a study by Ba et al. concluded that teen-clubs, clinical psychological support and self-reinforcement strategies improved ART adherence among adolescents [118]. In a study conducted in low and middle-income countries, only home-based care was statistically associated with ART adherence while other interventions such as SMS reminders, economic support, enhanced counselling and multi-month refills were not statistically associated with ART adherence among adolescents [13]. In contrast, ART adherence facilitators such as social support, secrecy or confidentiality, counselling, and ART education were effective and acceptable. This could be explained by the fact that ART adherence facilitators considered a holistic approach to improving ART adherence [125,126]. Rather than focusing on a specific adolescent aspect of ART adherence, as described in the interventions included in the meta-analysis, improving ART adherence may necessitate a more comprehensive approach. This is further demonstrated in the composite, which includes social barriers where ART adherence is low. A comprehensive approach to overcoming social barriers has shown that social support can improve ART adherence in adolescents. Although quantitative studies incorporating these adherence facilitators are required in Sub-Saharan Africa, a comprehensive approach should be considered to improve ART adherence in adolescents aged 10 to 19 years.
Stigma and discrimination, and lack of social support were mostly experienced and perceived by adolescents and had a negative impact on the treatment uptake and adherence. Stigma and discrimination were interrelated with other barriers (health system-related, patient-related, therapy-related, cultural, and economic barriers) perceived and experienced by adolescents and has a major contribution in the treatment uptake and adherence. Even though treatment uptake is an ultimate responsibility of adolescents, the clinic factors such as distance to the clinic, waiting time, health-workers perceived attitudes had a negative impact on the adherence rate of adolescents. The health system-related factors combined with the economic factors were also interrelated as without financial assistance, access to clinic or health facility is limited resulting to compromised ART adherence. Cultural barriers such as religion and use of traditional medicine facilitated by social barriers and therapy-related especially ART knowledge, side effects, WHO stage, stigma, and discrimination negatively impacted on the uptake and adherence of ART. Our study is consistent with studies that showed that personal beliefs, stigma, trust or satisfaction with health care workers, health service-related factors, and social support are main predictors for ART adherence [66,110,[125][126][127]. Nevertheless, findings of this review indicate that these barriers can be addressed through proving social support, ART education and counselling of ALHIV. The identified facilitators are consistent with findings of a systematic review including studies conducted between 2004 and 2016 in SSA, which identified 29 facilitators which were mainly aimed at supporting adolescents through peer, care-giver, health-care workers, counseling, religion and beliefs of adolescents [115].
Our systematic review has strengths and limitations. Firstly, a key strength is that we conducted a mixed method systematic review which allows for comprehensive analysis of ART adherence among adolescents. Secondly, the review builds and improves on previously conducted studies in the region which included less studies in their analysis. Thirdly, even though our review only included studies published in peer reviewed journals, being a mixed method systematic review justified the exclusion of unpublished literature. Fourthly, the use of a holistic quality appraisal process promoted the use of researchers' skills and judgement to assess value of contribution of each study. Therefore, the inclusion of all studies despite the quality assessment score allowed for contribution of each study to the knowledge pool thus valuable insight to the study subject. However, as a limitation of the review, only studies conducted in English were included yet there could be substantial evidence in missed studies conducted in other languages. Secondly, our review only included studies conducted from 2010 excluding previously conducted studies. Our review may therefore be missing other content of the subject matter which might still be applicable in the recent era and could have changed the perspective of the findings.

Conclusion
Multiple barriers to ART adherence have been reported among adolescents. These barriers negatively affect the uptake of ART and thereby the adherence to ART among adolescents. Nonetheless, several interventions aimed at improving ART adherence have been implemented in SSA. These interventions are aimed at creating a crucial support system for adolescents to address barriers to ART among adolescents. These barriers linked to lack of support systems either from caregivers, peers, the health system, and school environments. Despite the interventions, adolescents still present low ART adherence, viral load suppression and high lost to follow up and high unsuppressed viral load. This could be an indication of lack of adolescents input during the design of the intervention. A comprehensive approach may be the best way to improve ART adherence in adolescents aged 10 to 19 years. There is however a need for a study aimed at solely studying the influence of these interventions on the ART outcome.